(1) Field of the Invention
The present invention relates to novel prodrugs of cinnamide compounds and drugs containing the same as active ingredients. The prodrugs and the drugs are useful for treating diseases caused by amyloid β (hereinafter referred to as Aβ), which are represented by Alzheimer's disease, and are suitable for oral or parenteral administration. More specifically, the present invention relates to novel prodrugs of cinnamide compounds, pharmacologically acceptable salts thereof, and drugs containing the same as active ingredients, wherein water solubility of the cinnamide compounds is increased by converting the imidazole moiety of cinnamide compound molecules into a quaternary salt form.
(2) Description of Related Art
Aβ proteins, which are metabolites of amyloid precursor proteins (hereinafter referred to as APP), are thought to be highly involved in alteration or exfoliation of nerve cells and also in expression of dementia. The main components of the Aβ proteins are Aβ40 consisting of 40 amino acids and Aβ42 having additional two amino acids at the C-terminal of the Aβ40. These Aβ40 and Aβ42 are highly aggregative and are main components of senile plaques. Further, it is known that mutation in APP or a presenilin gene, which is observed in familial Alzheimer's disease, increases the amounts of these Aβ40 and Aβ42. Therefore, a compound which can inhibit the synthesis of Aβ40 and Aβ42 from APP is expected as a therapeutic or preventive agent for diseases caused by Aβ, such as Alzheimer's disease. The present inventors have found cinnamide compounds as non-peptide compounds inhibiting the synthesis of Aβ40 and Aβ42 and having excellent drug activity (for example, International Publication No. WO05/115990).
Generally, in some compounds, the usefulness as a drug is restricted by their low water solubility. For example, it is broadly known that some azole compounds, which are famous antifungal agents, have low water solubility and thereby are prevented from development as parenteral agents.
A method for solving this problem is disclosed in U.S. Pat. No. 6,235,728, for example. According to this, the water solubility of an azole antifungal agent can be increased by binding a phosphonooxymethyl group to the azole moiety. In addition, prodrugs having a similar phosphonooxymethyl group or derivatives thereof represented by the following formula are disclosed in Yasutsugu Ueda and 21 others, Phosphonomethyl Prodrugs of the Broad Spectrum antifungal Azole, Ravuconazole: Synthesis and Biological Properties. Bioorganic & Medicinal Chemistry Letters 2003, 13, 3669-3672.

Further, Professor Stella Valentino's team from the University of Kansas discloses in International Publication No. WO99/33846 (Claims, page 48, lines 3 to 10) the compound represented by the formula (VIa),
wherein, R1, R2 and R3 represent substituents containing the tertiary or secondary amine of a parent compound, and R4 and R5 are an organic or an inorganic residue. This compound is generally described as having an external anion (A) associated with a quaternary amine center and an external cation associated with a phosphate dual anionic charge (page 18, line 28 to page 24, line 11 in the specification). Among such compounds, examples of medicinal compounds having a quaternary amine classified as an aromatic species are illustrated in the specification at page 22, line 1 to page 23, line 3. Illustrated examples include, for instance, miconazole having an imidazolyl group.
However, this publication lacks any disclosure either in the illustrated compounds or in the compounds described in the Examples of a cinnamide derivative containing an imidazolyl group, which is a characteristic feature of the present invention, and fails to either disclose or suggest the compound according to the present invention.
In addition, in International Publication No. WO98/43970, compounds, for example, represented by the following formula are disclosed as prodrugs of antifungal compounds,
wherein R1 denotes an alkyl group or the like, R2 denotes a hydrogen atom, an alkyl group, or the like, and R7 denotes a triazolyl group, a tetrazolyl group, or the like.
As described above, though quaternary ammonium prodrugs of azole antifungal agents have been reported, quaternary salt prodrugs of phenylimidazole derivatives which are commonly observed in a cinnamide compound structure have not been reported yet.